Method for treating disease states in mammals with naphthalene lipoxygenase-inhibiting agents

ABSTRACT

Psoriasis in mammals is relieved by topically administering naphthalenes of the formula: ##STR1## wherein: R 1  is lower alkoxy or optionally substituted phenoxy, 
     R 2  is the same as R 1 , or R 2  is hydrogen, lower alkyl, optionally substituted phenyl or optionally substituted phenylalkyl, 
     R 3  is hydrogen, lower alkyl, lower alkoxy, halo, optionally substituted phenyl, optionally substituted phenyl-lower-alkyl or optionally substituted phenyl-lower-alkoxy, and m is 1 or 2; 
     both X groups are the same and X is either --C(O)OR 4  or --C(O)NR 5  R 6 , wherein 
     R 4  is alkyl, phenyl or benzyl optionally substituted with one or two lower alkyl groups, lower alkoxy groups or halo; and 
     R 5  and R 6  are independently hydrogen, lower alkyl, cycloalkyl or phenyl optionally substituted with one or two lower alkyl groups, lower alkoxy groups or halo. 
     The compounds of this invention are also useful for the treatment of disease-states caused by lipoxygenase activity in mammals, particularly 5-lipoxygenase activity, when administered systemically.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of U.S. patent application Ser. No.023,591, filed Mar. 9, 1987, now U.S. Pat. No. 4,786,652, the completedisclosure of which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to naphthalene derivatives which are useful in thetreatment of certain dermatological conditions and in inhibitinglipoxygenase activity, particularly 5-lipoxygenase activity. Thus thecompounds are useful both for topical treatment of inflammatory statesin mammals and for systemic treatment of a variety of disease-states(including inflammation) caused by lipoxygenase activity in mammals,particularly 5-lipoxygenase activity. This invention also relates topharmaceutical compositions useful in topically relieving the effects ofcertain chronic recurrent papulosquamous dermatoses, e.g., psoriasis,and in systemically relieving a variety of disease states (includinginflammatory states caused by an influx of leukocytes) caused bylipoxygenase activity, particularly 5-lipoxygenase activity. Thisinvention also relates to a process for preparing compounds of thisinvention.

2. Related Disclosures

Psoriasis is a skin disease characterized in part by excessiveproliferation of cells of the epidermis which remain strongly adherentand build up into a scaley plaque typical of the disease. Whilecurrently available therapies, such as corticosteroids, vitamin Aderivatives (retinoids), cancer chemotherapeutic agents (methotrexate,razoxane), coal tar and anthralin preparations, and psoralen-u.v.irradiation (PUVA) are effective in controlling the disease to a certainextent, they can cause numerous and sometimes severe undesirable sideeffects including renal irritation, hepatic toxicity, and erythema.

Certain naphthoquinone derivatives are known to be useful in treatingpsoriasis. See, for example, U.S. Pat. Nos. 4,229,478, 4,466,981 and4,593,120 and British Patent No. 1,243,401. Carbamate and carbonatederivatives of naphthalene having insecticidal properties are known.See, for example, U.S. Pat. Nos. 2,383,392, 3,958,006 and 4,181,741.Surprisingly, it has been discovered that the compounds of the instantinvention are also effective antipsoriatic agents. Compounds of formula(I) provide prolonged activity in the treatment of psoriasis because oftheir stability upon application and slow conversion to compounds offormula (XII) and (XIII). Further, the compounds of the presentinvention are more stable in the topical formulations normally used.

In addition, it has been surprisingly discovered that the compounds offormula (I) are systemically effective in the inhibition of lipoxygenaseactivity in mammals, particularly 5-lipoxygenase activity. They are thususeful in relieving a variety of disease-states, including inflammatorystates and hypersensitivity, caused by such lipoxygenase activity.

SUMMARY

The present invention relates to a compound of the formula ##STR2##wherein: R¹ is lower alkoxy of one to six carbon atoms or phenoxyoptionally substituted by one or two substituents chosen from loweralkyl of one to four carbon atoms, lower alkoxy of one to four carbonatoms and halo;

R² is the same as R¹, or R² is hydrogen, lower alkyl of one to sixcarbon atoms, phenyl or phenyl-lower-alkyl, wherein the phenyl ring ofthe phenyl or phenyl-lower-alkyl group is optionally substituted by oneor two substituents chosen from lower alkyl of one to four carbon atoms,lower alkoxy of one to four carbon atoms and halo;

R³ is hydrogen, halo, lower alkyl of one to six carbon atoms, loweralkoxy of one to six carbon atoms, phenyl, phenyl-lower-alkyl orphenyl-lower-alkoxy, wherein the phenyl ring of the phenyl,phenyl-lower-alkyl or phenyl-lower-alkoxy group is optionallysubstituted by one or two substituents chosen from lower alkyl of one tofour carbon atoms, lower alkoxy of one to four carbon atoms and halo;

m is 1 or 2; and

both X groups are the same and X is either --C(O)OR⁴ or --C(O)NR⁵ R⁶,wherein

R⁴ is alkyl of one to seven carbon atoms, phenyl or benzyl, wherein thephenyl ring of the phenyl or benzyl group is optionally substituted byone or two substituents chosen from lower alkyl of one to four carbonatoms, lower alkoxy of one to four carbon atoms and halo; and

R⁵ and R⁶ are independently hydrogen, lower alkyl of one to six carbonatoms, cycloalkyl of five to eight carbon atoms or phenyl optionallysubstituted with one or two substituents chosen from lower alkyl of oneto four carbon atoms, lower alkoxy of one to four carbon atoms and halo.

Another aspect of the invention is a method for relieving inflammatorydiseases such as the condition of psoriasis in a mammal which comprisestopically administering to said mammal an antiinflammatory amount of acompound of formula (I).

Yet another aspect of the invention is a method for relieving a varietyof disease-states, including the conditions of inflammation andhypersensitivity, caused by lipoxygenase activity in a mammal,particularly 5-lipoxygenase activity, which method comprisessystemically administering to the said mammal a lipoxygenase inhibitingamount of a compound of formula (I).

A further aspect of the present invention relates to a pharmaceuticalcomposition in a form suitable for topical administration to mammalscomprising a compound of the formula (I) in admixture with one or morepharmaceutically acceptable non-toxic carriers.

Still another aspect of the present invention relates to apharmaceutical composition in a form suitable for systemicadministration to mammals comprising a compound of the formula (I) inadmixture with one or more pharmaceutically acceptable non-toxiccarriers.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENT

In its broadest aspect, the present invention relates to compounds ofthe formula ##STR3## wherein: R¹ is lower alkoxy of one to six carbonatoms or phenoxy optionally substituted by one or two substituentschosen from lower alkyl of one to four carbon atoms, lower alkoxy of oneto four carbon atoms and halo;

R² is the same as R¹, or R² is hydrogen, lower alkyl of one to sixcarbon atoms, phenyl or phenyl-lower-alkyl, wherein the phenyl ring ofthe phenyl or phenyl-lower-alkyl group is optionally substituted by oneor two substituents chosen from lower alkyl of one to four carbon atoms,lower alkoxy of one to four carbon atoms and halo;

R³ is hydrogen, halo, lower alkyl of one to six carbon atoms, loweralkoxy of one to six carbon atoms, phenyl, phenyl-lower-alkyl orphenyl-lower-alkoxy, wherein the phenyl ring of the phenyl,phenyl-lower-alkyl or phenyl-lower-alkoxy group is optionallysubstituted by one or two substituents chosen from lower alkyl of one tofour carbon atoms, lower alkoxy of one to four carbon atoms and halo;

m is 1 or 2; and

both X groups are the same and X is either --C(O)OR⁴ or --C(O)NR⁵ R⁶,wherein

R⁴ is alkyl of one to seven carbon atoms, phenyl or benzyl, wherein thephenyl ring of the phenyl or benzyl group is optionally substituted byone or two substituents chosen from lower alkyl of one to four carbonatoms, lower alkoxy of one to four carbon atoms and halo; and

R⁵ and R⁶ are independently hydrogen, lower alkyl of one to six carbonatoms, cycloalkyl of five to eight carbon atoms or phenyl optionallysubstituted with one or two substituents chosen from lower alkyl of oneto four carbon atoms, lower alkoxy of one to four carbon atoms and halo.

The present invention also relates to a method for relievinginflammatory diseases such as the condition of psoriasis in a mammalwhich comprises topically administering to said mammal anantiinflammatory amount of a compound of formula (I).

Yet another aspect of the invention is a method for relieving a varietyof disease-states, including the conditions of inflammation andhypersensitivity, caused by lipoxygenase activity in a mammal,particularly 5-lipoxygenase activity, which comprises systemicallyadministering to said mammal a lipoxygenase inhibiting amount of acompound of formula (I).

A further aspect of the present invention relates to a pharmaceuticalcomposition in a form suitable for topical administration to mammalscomprising a compound of the formula (I) in admixture with one or morepharmaceutically acceptable non-toxic carriers.

Still another aspect of the present invention relates to apharmaceutical composition in a form suitable for systemicadministration to mammals comprising a compound of the formula (I) inadmixture with one or more pharmaceutically acceptable non-toxiccarriers.

The compounds of formula (I) may be divided into subgroups (Ia) and(Ib).

Compounds of subgroup (Ia) are represented by formula (I) wherein X is--C(O)NR⁵ R⁶ wherein R⁵ and R⁶ are as defined above. Within thissubgroup it is preferred that R¹ is methoxy or ethoxy, R² is methoxy,ethoxy, hydrogen or methyl, R⁵ is hydrogen and R⁶ is methyl or ethyl,with R¹ and R² being methoxy being the most preferred.

Compounds of subgroup (Ib) are represented by formula (I) wherein X is--C(O)OR⁴ wherein R⁴ is as defined above. Within this subgroup it ispreferred that R¹ is methoxy or ethoxy, R² is methoxy, ethoxy, hydrogenor methyl and R⁴ is methyl or ethyl, with R¹ and R² being methoxy beingthe most preferred.

An even more specific embodiment of the instant invention are compoundsof formula (I) wherein m is 1 and R³ is at the 6-position and is bromo,chloro, fluoro, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, andi-butoxy, with chloro being preferred.

A preferred embodiment of the invention are compounds of formula (I)wherein R³ is hydrogen.

Another embodiment of the invention are compounds wherein m is 2 and thetwo R³ groups are at the 6 and 7 positions and are lower alkyl, loweralkoxy or halo with R³ being methyl being preferred.

In the present specification and claims the term "alkyl" is intended tomean alkyl groups containing one to seven carbon atoms includingstraight chain groups, or branched chain groups. Illustrative of suchgroups are for example, methyl, ethyl, n-propyl, i-propyl, n-hexyl,2-methylpentyl, n-heptyl, 2,2-dimethylbutyl and 3,3-dimethylpentyl. Theterm "lower alkyl" refers to alkyl groups of one of six carbon atoms asdefined above. Examples of "lower alkyl" groups are methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, 2,2-dimethylpropyl andt-hexyl. The term "phenyl-lower-alkyl" refers to an optionallysubstituted phenyl ring attached to an alkylene chain of one to sixcarbon atoms.

The term "lower alkoxy" refers to a straight or branched chain aliphaticgroup of one to six carbon atoms having bonded thereto an oxygen moiety.Examples of "lower alkoxy" are methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, s-butoxy, t-butoxy and n-pentyloxy."Phenyl-lower-alkoxy" refers to a phenyl ring attached to an alkylenechain of one to six carbon atoms having bonded thereto an oxygen atom.Examples of "phenyl-lower-alkoxy" are benzyloxy, 4-chlorophenylethoxy,phenyl-n-prooxy and 2-methoxyphenyl-n-hexyloxy.

The term "sterically hindered" refers to alkyl groups wherein branchingoccurs at the carbon adjacent to or one carbon removed from the carbonylgroup or to optionally substituted phenyl.

Optionally substituted phenyl refers to a phenyl ring optionallysubstituted by one or more substituents selected from the groupconsisting of lower alkyl, lower alkoxy and halo unless otherwisedefined.

The term "halo" refers to fluoro, chloro, and bromo.

The term "treatment" as used herein covers any treatment of a disease ina mammal, particularly a human, and includes:

(i) preventing the disease from occurring in a subject which may bepredisposed to the disease but has not yet been diagnosed as having it;

(ii) inhibiting the disease, i.e., arresting its development; or

(iii) relieving the disease, i.e., causing regression of the disease.

It is possible that the preparation of compounds of formula (II) whereboth R² and R³ are other than hydrogen may give rise to a mixture of twoisomers, i.e. the two isomers where R² is at the 2- or the 3-position ofthe compound of formula (II). Without separation, this would leadeventually to a mixture of 2- and 3-isomers of the compound of formula(I). In the event that such a mixture is obtained, the isomers may beseparated by crystallization, normal or reverse phase HPLC or otherpartition chromatographic techniques, and the like. The claims andspecification of this patent application are intended to encompass eachindividual isomer of formula (I) alone or in combination with itscorresponding isomer, unless specifically designated otherwise.

FORMULATION AND ADMINISTRATION

The compositions of the present invention may be formulated foradministration in any convenient way by analogy with other topicalcompositions adapted for use in mammals. These compositions may bepresented for use in any conventional manner with the aid of any of thewide variety of pharmaceutical carriers or vehicles.

The naphthalenes of formula (I) may be formulated with suitablepharmaceutical vehicles known in the art to form particularly effectivetopical compositions. An effective amount of the naphthalene compoundsis about 0.001% w to about 10% w of the total formulated composition.The rest of the formulated composition will be about 90% w to about99.999% w of a suitable excipient which may include a pharmaceuticallyacceptable solvent and other pharmaceutically acceptable additives toform a topically effective pharmeceutical formulation.

A pharmaceutically acceptable solvent is one which is substantiallynon-toxic and non-irritating under the conditions used and may bereadily formulated into any of the classical drug formulations such aspowders, creams, ointments, lotions, gels, foams, aerosols, solutionsand the like. Particularly suitable solvents include water, ethanol,acetone, glycerine, propylene carbonate, dimethylsulfoxide (DMSO), andglycols such as 1,2-propylene diol, i.e., propylene glycol,1,3-propylene diol, polyethylene glycol having a moleuclar weight offrom 100 to 10,000, dipropylene glycol, etc. and mixtures of theaforementioned solvents with each other.

A topical cream may be prepared as a semi-solid emulsion of oil in wateror water in oil. A cream base formulation by definition is an emulsion,which is a two-phase system with one liquid (for example fats or oils)being dispersed as small globules in another substance (e.g., aglycol-water solvent phase) which may be employed as the primary solventfor the naphthalenes therein. The cream formulation may contain fattyalcohols, surfactants, mineral oil or petrolatum and other typcialpharmaceutical adjuvants such as anti-oxidants, antiseptics, orcompatible adjuvants. A typical cream base formulation is as follows:

    ______________________________________                                        Water/glycol mixture                                                                           50-99     parts by weight                                    (15% or more glycol)                                                          Fatty Alcohol     1-20                                                        Non-ionic Surfactant                                                                            0-10                                                        Mineral Oil       0-10                                                        Typical Pharmaceutical                                                                         0-5                                                          Adjuvants                                                                     Active Ingredients                                                                             0.001-10                                                     ______________________________________                                    

The fatty alcohol, non-ionic surfactant, and other adjuvants arediscussed in U.S. Pat. No. 3,934,013 to Poulsen.

The naphthalenes of formula (I) may also be formulated as topicalointments. A "classical" ointment is a semisolid anhydrous compositionwhich may contain mineral oil, white petrolatum, a suitable solvent suchas a glycol and may include propylene carbonate and otherpharmaceutically suitable additives such as surfactants, for exampleSpan and Tween, or wool fat (lanoline), along with stabilizers such asantioxidants and other adjuvants as mentioned before. Following is anexample of a typical "classical" ointment base:

    ______________________________________                                        White Petrolatum 40-94     parts by weight                                    Mineral Oil       5-20                                                        Glycol Solvent    1-15                                                        Surfactant        0-10                                                        Stabilizer        0-10                                                        Active Ingredients                                                                             0.001-10.0                                                   ______________________________________                                    

Other suitable ointment base formulations which employ propylenecarbonate are described in U.S. Pat. No. 4,071,615 issued Apr. 12, 1977by Shastri et al entitled "Propylene Carbonate Ointment Vehicle" andU.S. Pat. No. 3,924,004 issued Dec. 2, 1975 by Chang et al entitled"Fatty Alcohol-Propylene Carbonate-Glycol Solvent Cream Vehicle".Following is a typical ointment base formulation containing propylenecarbonate:

    ______________________________________                                        Active Ingredients                                                                             0.001-10.0                                                                              parts by weight                                    Propylene Carbonate                                                                             1-10                                                        Solvent           1-10                                                        Surfactant        0-10                                                        White Petrolatum 70-97                                                        ______________________________________                                    

Suitable solvents, surfactants, stabilizers, etc. are discussed in U.S.Pat. No. 3,934,013.

A suitable topical "non-classical" anhydrous, water washable "ointmenttype" base is described in U.S. Pat. No. 3,592,930 to Katz and Neiman. Arepresentative composition of this invention utilizing such base is asfollows:

    ______________________________________                                        Glycol Solvent   40-35     parts by weight                                    Fatty Alcohol    15-45                                                        Compatible Plasticizer                                                                          0-15                                                        Compatible Coupling                                                                             0-15                                                        Agent                                                                         Penetrant         0-20                                                        Active Ingredients                                                                             0.001-10.0                                                   ______________________________________                                    

Another aspect of the invention is a method for relieving the conditionof psoriasis in a mammal by topically administering a compositioncontaining a compound of formula (I) wherein R¹, R², R³, X, Y and m areas defined above. Generally, the anti-psoriatic manifestation inmammals, particularly humans, is combatted by contacting the inflamedareas with a therapeutically effective amount of thenaphthalene-containing compositions of this invention, that is, anamount which results in a lessening of the epidermal cell proliferation(an anti-psoriatic effect). Preferably the naphthalenes are firstformulated to prepare a suitable pharmaceutical formulation, asdiscussed hereinabove, which is then placed in contact with theafflicted area(s). An effective amount of the naphthalene compound willdepend upon the particular condition and the mammal receiving thetreatment and will vary between 0.001% to 10% by weight of thepharmaceutical composition and preferably will be between 0.01% and 1%by weight of the formulation. Using these levels in the formulation, atherapeutically effective and non-side effect producing amount, i.e.enough to affect an anti-psoriatic response, but not enough to adverselyeffect the recipient, is applied to the afflicted area(s).

The compounds of the present invention have also been found to be activewhen administered systemically for the treatment of mammals having avariety of disease-states caused by lipoxygenase activity, particularly5-lipoxygenase activity. Accordingly, the compounds may be formulated asoral, parenteral and otherwise systemic compositions. Depending on theintended mode, the compositions may be in the form of solid, semi-solidor liquid dosage forms, such as, for example, tablets, suppositories,pills, capsules, powders, liquids, suspensions, or the like, preferablyin unit dosage forms suitable for single administration of precisedosages. The compositions will include a conventional pharmaceuticalcarrier or excipient and a therapeutically effective amount of acompound of formula (I) and, in addition, may include other medicinalagents, pharmaceutical agents, carriers, adjuvants, etc.

The amount of active compound administered will of course, be dependenton the subject being treated, the severity of the affliction, the mannerof administration and the judgment of the prescribing physician.

Typical compositions contain 0.01-95% by weight of active ingredient,with the balance one or more acceptable non-toxic carriers. Thepercentage of active ingredient, will, of course, depend upon the dosageform and the mode of administration.

For solid compositions, conventional non-toxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talcum, cellulose, glucose,sucrose, magnesium carbonate, and the like may be used. The activecompound as defined above may be formulated as suppositories using, forexample, polyalkylene glycols, for example, propylene glycol, as thecarrier. Liquid pharmaceutically administerable compositions can, forexample, be prepared by dissolving, dispersing, etc. an active compoundas defined above and optional pharmaceutical adjuvants in a carrier,such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form a solution or suspension. Ifdesired, the pharmaceutical composition to be administered may alsocontain minor amounts of nontoxic auxiliary substances such as wettingor emulsifying agents, pH buffering agents and the like, for example,sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate,triethanolamine oleate, etc. Actual methods of preparing such dosageforms are known, or will be apparent, to those skilled in this art; forexample, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 15th Edition, 1975. The composition or formulationto be administered will, in any event, contain a quantity of the activecompound(s) in an amount effective to alleviate the symptoms of thesubject being treated.

For oral administration, a pharmaceutically acceptable non-toxiccomposition is formed by the incorporation of any of the normallyemployed excipients, such as, for example, pharmaceutical grades ofmannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum,cellulose, glucose, sucrose, magnesium, carbonate, and the like. Suchcompositions take the form of solutions, suspensions, tablets, pills,capsules, powders, sustained release formulations and the like. Suchcompositions may contain 2-95% active ingredient, preferably 5-25%.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol or the like. Inaddition, if desired, the pharmaceutical compositions to be administeredmay also contain minor amounts of non-toxic auxiliary substances such aswetting or emulsifying agents, pH buffering agents and the like, such asfor example, sodium acetate, sorbitan monolaurate, triethanolamineoleate, etc.

For systemic administration via suppository, traditional binders andcarriers include, e.g. polyalkalene glycols or triglycerides. Suchsuppositories may be formed from mixtures containing active ingredientin the range of 0.1%-10%; preferably 0.5 to 2%.

In vitro lipoxygenase inhibiting activity of the compounds of thisinvention are determined by the standard Human PolymorphonuclearLeukocytes assay. This assay is a modification of that described by O.Radmark, C. Malmsten, and B. Samuelsson in FEBS Letter, 110, 213-215,1980. In vivo lipoxygenase inhibiting activity of the compounds of thisinvention are determined by the arachidonic acid mouse ear inflammationassay as described by J. M. Young, D. A. Spires, C. J. Bedord, B.Wagner, S. J. Ballaron and L. M. DeYoung in Journal of InvestigativeDermatology, 82, 367-371, 1984.

PREPARATION

The compounds of formula (I) where R¹ and R² are the same and are loweralkoxy or optionally substituted phenoxy may be prepared fromintermediates of formula (V), (where R¹ and R² are as defined above),the preparation of which is shown below in Reaction Sequence I. ##STR4##wherein R¹ and R² are the same and are lower alkoxy or optionallysubstituted phenoxy, A is chlorine or bromine and R³ is as definedabove.

The intermediates of formula (II), where R² is hydrogen and R³ is asdefined above, are prepared according to the method disclosed in J. Am.Chem. Soc., 70, 3165 (1948) and Ibid., 71, 3615 (1949). A butadienesubstituted with the appropriate embodiment of R³ is reacted with1,4-benzoquinone in a solvent such as acetic acid at a temperature of-10° C. to 30° C., preferably at 25° C. for 24 to 72 hours, preferablyfrom 40 to 48 hours. The 5,8-dihydro derivative of the compound offormula (II) is recovered and treated with an oxidizing agent such assodium dichromate, sodium nitrite, manganese dioxide and the like toform compounds of formula (II) where R² is hydrogen.

Compounds of formula (III) are prepared by reacting the compound offormula (II) with chlorine or bromine, preferably chlorine. For example,chlorine gas is bubbled into a solution of the compound of formula (II)dissolved in a solvent such as glacial acetic acid, nitrobenzene, carbontetrachloride and the like, preferably glacial acetic acid at refluxtemperature in the presence of a suitable catalyst such as sodiumacetate, iodine, iron(III) chloride, dimethylformamide or loweralcohols, for example methanol or ethanol, preferably about 0.1 molarequivalent of iodine. The compound of formula (III) where R³ is hydrogenand A is chlorine is commercially available from, i.a., Aldrich ChemicalCo.

Compounds of formula (IV) are prepared from the 2,3-dihalonaphthoquinoneof formula (III), preferably a 2,3-dichloro-1,4-naphthoquinone. Thecompound of formula (III) is reacted with an alkali metal alkoxide orphenoxide of formula R¹ M, where M is an alkali metal. The reaction isconducted in an inert organic solvent such as tetrahydrofuran,dimethylsulfoxide, dimethylformamide and the like, or preferably in analcohol of formula R¹ H, at temperatures from about 20° C. to about 100°C., preferably about 60°-70° C., for a time sufficient to assurecompleteness of reaction, i.e., for about 30 minutes to about 8 hours,preferably about 1-2 hours. When the reaction is substantially completethe compound of formula (IV), where R¹ and R² are the same, is isolatedby conventional means, such as crystallization.

Compounds of formula (IV) are then reduced to compounds of formula (V).The compound of formula (IV) may be hydrogenated in a hydrogenatmosphere in the presence of a catalyst such as palladium on charcoal,or alternatively reduced using transfer hydrogenation conditions with,for example, cyclohexadiene and a catalyst such as palladium oncharcoal. Polar solvents such as tetrahydrofuran, dimethylformamide orethanol are preferred, most preferably tetrahydrofuran. Alternatively,the compounds of formula (IV) are reduced with sodium hydrosulfite in analcoholic solvent, for example methanol or ethanol, to give the compoundof formula (V) where R¹ and R² are the same and are lower alkoxy oroptionally substituted phenoxy.

The compounds of formula (I) where R¹ is lower alkoxy or optionallysubstituted phenoxy, and R² is hydrogen, lower alkyl, optionallysubstituted phenyl or optionally substituted phenylalkyl may be preparedfrom intermediates of formula (V), (where R¹ and R² are as definedabove), the preparation of which is shown below in Reaction Sequence II.##STR5##

The intermediates of formula (II), where R² is hydrogen and R³ is asdefined above are prepared according to the method disclosed in ReactionSequence I, supra. Compounds of formula (II) wherein R² is alkyl,optionally substituted phenyl or phenylalkyl may be prepared by reactingthe naphthoquinone of formula (II) wherein R² is hydrogen with an acidof the formula R² COOH wherein R² is as defined above but is other thanhydrogen. A solution of the acid and naphthoquinone in acetonitrile andsulfolane in the presence of a metal nitrate, e.g. silver nitrate andthe like, is heated to 50°-100° C., preferably to 55°-75° C. A solutionof a persulfate salt, e.g. diammonium persulfate, is added dropwise.Compounds of formula (II) wherein R² is alkyl, optionally substitutedphenyl or phenylalkyl are recovered by conventional means such aschromatography.

Compounds of formula (VI) are prepared by bubbling chlorine gas into asolution of compound of formula (II) dissolved in a solvent such asglacial acetic acid, nitrobenzene, carbon tetrachloride and the like,preferably glacial acetic acid maintained at about 15° C. The compoundof formula (VI), which may be isolated by known means, dissolved in asolvent such as acetic acid is treated with a suitable catalyst such assodium acetate, iodine, iron(III)chloride, dimethylformamide or loweralcohols, for example methanol or ethanol, with heating under reflux for1/2 to 4 hours, preferably for 1 to 21/2 hours to yield compounds offormula (VII).

Compounds of formula (VIII) are prepared by reacting compound of formula(VII) with an alkali metal alkoxide or phenoxide such as sodium alkoxideor phenoxide, e.g. sodium methoxide or phenoxide in an anhydrous solventsuch as methanol, dimethylformamide, tetrahydrofuran and the like, thesolvent if an alcohol being chosen according to the length of the alkylchain on the alkoxy group e.g. sodium methoxide in methanol, sodiumethoxide in ethanol and the like. The reaction mixture is stirred at atemperature of about 0° C. to 60° C., preferably about 25° C., for about3 hours to 24 hours, preferably for about 10 to 18 hours. Compounds offormula (VIII) are recovered by conventional means such as bycrystallization.

Compounds of formula (VII) may also be converted to compounds of formula(VIII), by treatment with an alcoholic solution of a strong base such aspotassium hydroxide in methanol and then alkylating the intermediatecompound of formula (X), infra, using the appropriate halide or analcohol as is described hereinafter under Reaction Sequence III.

Compounds of formula (VIII) are then reduced to compounds of formula(V). The compound of formula (VIII) may be hydrogenated in a hydrogenatmosphere in the presence of a catalyst such as palladium on charcoal,or alternatively reduced using transfer hydrogenation conditions with,for example, cyclohexadiene and a catalyst such as palladium oncharcoal. Polar solvents such as tetrahydrofuran, dimethylformamide orethanol are preferred, most preferably tetrahydrofuran. Alternatively,the compounds of formula (VIII) are reduced with sodium hydrosulfite inan alcoholic solvent, for example methanol or ethanol. Thus thecompounds of formula (V) are obtained, where R¹ is lower alkoxy oroptionally substituted phenoxy, and R² is hydrogen, lower alkyl,optionally substituted phenyl or optionally substituted phenylalkyl.

An alternative method for preparing the compounds of formula (VIII)where R¹ is lower alkoxy or optionally substituted phenoxy, and R² ishydrogen, lower alkyl, optionally substituted phenyl or optionallysubstituted phenylalkyl is depicted in Reaction Sequence III below.##STR6## wherein R¹, R², R³ and m are as defined above.

The compound of formula (IX) is prepared by acylating the compound offormula (II) in the presence of a Lewis acid such as borontrifluoride:etherate or a strong inorganic acid, such as perchloricacid, and the like. This reaction is commonly known as the Theile-Winterreaction. The acylating agent is an acid anhydride such as aceticanhydride, propanoic anhydride and the like, preferably aceticanhydride. The compound of formula (IX) wherein R² is hydrogen may beconverted to the compound of formula (IX) wherein R² is alkyl,optionally substituted phenyl or phenylalkyl by reaction with a peracidanhydride of the formula (R₂ CO₂)₂ wherein R² is as defined above and isother than hydrogen. A solution of the unsubstituted compound in asolvent such as glacial acetic acid is heated to 70°-120° C., preferablyfrom 75°-100° C. and an ethereal solution of the anhydride is addeddropwise over 1 to 6 hours, preferably over 2 to 4 hours. The compoundof formula (IX) wherein R² is alkyl, optionally substituted phenyl orphenylalkyl is recovered by precipitation. The compound of formula (IX)wherein R² is hydrogen or alkyl, optionally substituted phenyl oroptionally substituted phenylalkyl is then hydrolyzed by treatment withan alkali metal alkoxide in an alcohol, such as sodium methoxide inmethanol, followed by treatment with aqueous hydrochloric acid to formthe compound of formula (X).

The compound of formula (X) is then converted to the compound of formula(VIII), where R¹ is lower alkoxy or optionally substituted phenoxy, andR² is hydrogen, lower alkyl, optionally substituted phenyl or optionallysubstituted phenylalkyl, by reaction with an appropriate halide andbase.

The compound of formula (X) is reacted with an alkyl halide, e.g. analkyl bromide or alkyl iodide, or a phenylalkyl halide, in a solventsuch as tetrahydrofuran and the like. A solution of1,5-diazobicyclo[5.4.0]undec-5-ene (DBU) in a solvent such astetrahydrofuran is added dropwise. The precipitate of DBU-hydrogenhalide which forms is removed by filtration and the compound of formula(VIII) is recovered by evaporation.

The compound of formula (VIII) may also be prepared by reacting thecompound of formula (X) with an alcohol such as methanol or ethanol. Toa solution of the compound of formula (X) in the appropriate alcohol offormula R¹ H is added boron trifluoride:etherate. The solution is heatedfrom 50° to 100° C., preferably from 60° to 80° C. for 1/2 hour to 4hours, preferably for 1 to 3 hours. The compound of formula (VIII) isrecovered by filtration.

Compounds of Formula I

Compounds of formula (Ia) where X is --C(O)NR⁵ R⁶ may be prepared by themethods depicted in Reaction Sequences (IVA), (IVB) and (IVC) below.##STR7##

In Reaction Sequence IVA, the preparation starts from the compound offormula (V), prepared as shown in Reaction Sequences I, II and III. Toprepare the compound of formula (Ia), where X is --C(O)NR⁵ R⁶, thecompound of formula (V) is first converted to an activated carbonylderivative of formula (XI), in which Z is a leaving group chosen to becapable of displacement by an amine of formula HNR⁵ R⁶. For example, Zmay be halo, 1-imidazolyl, trichloromethoxy, optionally substitutedphenoxy, such as 2,4-dichlorophenoxy, 4-methoxyphenoxy, and the like.For example, the compound of formula (XI) where Z is chloro is made byreaction of a compound of formula (V) with from 1-10 molar equivalents,preferably about 2 molar equivalents, of phosgene in an inert organicsolvent such as benzene, acetonitrile, ethyl acetate, tetrahydrofuran,diethyl ether, chloroform, methylene chloride and the like, preferablybenzene. The reaction takes place in the presence of from 1-5 molarequivalents, preferably about 2 molar equivalents of a tertiary organicbase such as triethylamine or preferably pyridine. The reaction isconducted at from 0°-50° C., preferably about 20°-30° C., for about 1-72hours, preferably about 16-24 hours, and then filtered. Evaporation ofthe filtrate under vacuum affords the compound of formula (XI) where Zis chloro.

Alternatively, the compound of formula (V) is reacted as above,substituting an appropriately substituted alkyl or aryl chloroformatefor phosgene, giving the compound of formula (XI) where Z is thecorrespondingly substituted alkoxy or aryloxy leaving group.

Alternatively, the compound of formula (V) is reacted as above,substituting N,N'-carbonyldiimidazole for phosgene, giving the compoundof formula (XI) where Z is 1-imidazolyl.

Compounds of formula (Ia) are then prepared by treating theappropriately substituted compound of formula (XI) with an appropriateamine of formula HNR⁵ R⁶, thereby converting the --OC(O)Z group to thecorresponding carbamate. To carry out this process, the compound offormula (XI) is dissolved in an inert solvent as defined above,preferably tetrahydrofuran, and reacted with from about 2-5 molarequivalents, preferably about 2-3 molar equivalents, of the appropriateamine of formula HNR⁵ R⁶ in solution in an inert solvent as definedabove, preferably tetrahydrofuran. The reaction takes place at atemperature of about 0°-40° C., preferably about 20°-30° C., for about1-10 hours, preferably about 4-6 hours. When the reaction issubstantially complete, the product compound of formula (Ia) is isolatedby conventional means such as chromatography.

Alternatively, the reaction is carried out in the presence of from 1-5molar equivalents, preferably 2 molar equivalents, of a tertiary organicbase or an inorganic base, as defined above. The compound of formula(XI) is reacted in the presence of the base with from 1-4 molarequivalents, preferably about 1.2 molar equivalents, of the appropriateamine of formula HNR⁵ R⁶ in an inert organic solvent, as defined above.

Alternatively, as shown in Reaction Sequence IVB, compounds of formula(Ia) are made directly from compounds of formula (V), by reaction withan appropriately substituted carbamoyl chloride of formula ClC(O)NR⁵ R⁶,where R⁵ and R⁶ cannot both be hydrogen. To carry out this process, thecompound of formula (V) is dissolved in an inert organic solvent asdefined above, preferably tetrahydrofuran, and reacted with from 1-4molar equivalents, preferably about 1.2 molar equivalents, of theappropriate carbamoyl chloride of formula ClC(O)NR⁵ R⁶ in the presenceof a tertiary organic base or inorganic base as defined above. Thereaction takes place at a temperature of about 0°-40° C., preferablyabout 20°-30° C., for about 1-10 hours, preferably about 4-6 hours. Whenthe reaction is substantially complete, the product of formula (Ia) isisolated by conventional means such as chromatography.

As shown in Reaction Sequence IVC, compounds of formula (Ia) where R⁶ ishydrogen can be made by reacting a compound of formula (V) with anappropriately substituted isocyanate of formula R⁵ NCO where R⁵ is nothydrogen. To carry out this process, the compound of formula (V) isdissolved in an inert organic solvent as defined above, preferablytetrahydrofuran, and reacted with from 1-5 molar equivalents, preferablyabout 1.2 molar equivalents, of an isocyanate of formula R⁵ NCO in thepresence of about 0.2 molar equivalents of 4-dimethylaminopyridine. Thereaction takes place at a temperature of about 10°-70° C., preferablyabout 45°-55° C., for about 4-48 hours, preferably about 18-24 hours.When the reaction is substantially complete, the product of formula (Ia)is isolated by conventional means such as chromatography.

Compounds of formula (Ib) where X is --C(O)OR⁴ may be prepared by themethods depicted in Reaction Sequences (VA) and (VB) below. ##STR8##

As shown in Reaction Sequence VA, to prepare the compound of formula(Ib), where X is --C(O)OR⁴, the activated carbonyl derivative of formula(XI), prepared as shown in Reaction Sequence IVA above, is reacted withan alcohol of formula R⁴ OH. To carry out this process the compound offormula (XI) is dissolved in an alcohol of formula R⁴ OH containing from1-5 molar equivalents, preferably about 2 molar equivalents of atertiary organic base such as triethylamine or preferably pyridine. Thereaction takes place at a temperature of about 0°-40° C., preferablyabout 20°-25° C., for about 1-10 hours, preferably about 4-6 hours. Whenthe reaction is substantially complete, the product compound of formula(Ib) is isolated by conventional means.

Alternatively, as shown in Reaction Sequence VB, the compound of formula(V) is reacted as shown above in Reaction Sequence IVA with anappropriate alkyl or aryl chloroformate, or alternatively with anappropriate dialkyl or diaryl dicarbonate, in the presence of a tertiaryorganic base. For example, the compound of formula (V) is dissolved inan inert solvent as defined above, preferably tetrahydrofuran, andreacted with a chloroformate and a tertiary organic base, preferablytriethylamine. The reaction is conducted at a temperature of about0°-50° C., preferably about 20°-25° C., for about 4-48 hours, preferablyabout 18-24 hours, giving the compound of formula (Ib), which isisolated by conventional means.

Preparation of Starting Materials

The compounds of formula HNR⁵ R⁶ are commercially available from, i.a.,Aldrich Chemical Co.. Alternatively, they can be prepared by standardmethods known to those skilled in the chemical art.

The compounds of formula ClC(O)NR⁵ R⁶ are either available commerciallyfrom, i.a., Aldrich Chemical Co. or they can be prepared by, forexample, reaction of a secondary amine of formula HNR⁵ R⁶ with phosgene.Compounds of formula ClC(O)NR⁵ R⁶ wherein R⁵ is hydrogen can be preparedby the reaction of an isocyanate of formula R⁶ NCO, where R⁶ is nothydrogen, with an excess of dry hydrochloric acid in an inert solvent.These reactions are described in greater detail in Comprehensive OrganicChemistry, Vol. 2, by Barton and Ollis, pp. 1088-1090.

Any alkyl or aryl chloroformates that are not commercially available areprepared, for example, by reaction of phosgene with one equivalent ofthe appropriate alcohol or phenol in the presence of a base. Thereactions are described in greater detail in Comprehensive OrganicChemistry, by Barton and Ollis, Vol 2, pp 1078-1083 and Vol 3, pp 432-4.

The compounds of formula R⁶ NCO, where R⁶ is not hydrogen, that are notcommercially available are prepared by reaction of an appropriatelysubstituted primary amine (R⁶ NH₂) with phosgene. The reaction isdiscussed in further detail in Organic Functional Group Preparations,2nd Edition, Vol. 1, by Sandler and Karo, pp. 364-365.

In summary, the compounds of the present invention are made by theprocedures below:

1. The process for preparing compounds of formula (Ia) wherein:

R¹ is lower alkoxy of one to six carbon atoms or phenoxy optionallysubstituted by one or two substituents chosen from lower alkyl of one tofour carbon atoms, lower alkoxy of one to four carbon atoms and halo;

R² is the same as R¹, or R² is hydrogen, lower alkyl of one to sixcarbon atoms, phenyl or phenyl-lower-alkyl, wherein the phenyl ring ofthe phenyl or phenyl-lower-alkyl group is optionally substituted by oneor two substituents chosen from lower alkyl of one to four carbon atoms,lower alkoxy of one to four carbon atoms and halo;

R³ is hydrogen, halo, lower alkyl of one to six carbon atoms, loweralkoxy of one to six carbon atoms, phenyl, phenyl-lower-alkyl orphenyl-lower-alkoxy, wherein the phenyl ring of the phenyl,phenyl-lower-alkyl or phenyl-lower-alkoxy group is optionallysubstituted by one or two substituents chosen from lower alkyl of one tofour carbon atoms, lower alkoxy of one to four carbon atoms and halo;

m is 1 or 2; and

X is the same and is --C(O)NR⁵ R⁶, wherein R⁵ and R⁶ are independentlyhydrogen, lower alkyl of one to six carbon atoms, cycloalkyl of five toeight carbon atoms or phenyl optionally substituted with one or twosubstituents chosen from lower alkyl of one to four carbon atoms, loweralkoxy of one to four carbon atoms and halo; which comprises:

(a) reacting a compound of the formula ##STR9## wherein R¹, R², R³ and mare as defined above, with an isocyanate of the formula R⁶ NCO, where R⁶is as defined above but is not hydrogen, or

(b) reacting a compound of the formula (V) with a carbamoyl chloride ofthe formula ClC(O)NR⁵ R⁶, where R⁵ and R⁶ are as defined above but R⁶ isnot hydrogen.

2. Alternatively, the process for the preparation of the compounds ofthe formula (Ia), which comprises:

reacting a compound of the formula ##STR10## wherein R¹, R², R³ and mare as defined above, and --C(O)Z is an activated carbonyl complex whereZ is as defined supra, with an appropriate amine of the formula HNR⁵ R⁶,where R⁵ and R⁶ are as defined above.

3. The process for the preparation of the compounds of the formula (Ib),wherein R¹, R², R³ and m are as defined above, and X is the same and is--C(O)R⁴, where R⁴ is alkyl of one to seven carbon atoms, phenyl orbenzyl, wherein the phenyl ring of the phenyl or benzyl group isoptionally substituted by one or two substituents chosen from loweralkyl of one to four carbon atoms, lower alkoxy of one to four carbonatoms and halo; which comprises:

reacting a compound of the formula ##STR11## wherein R¹, R², R³ and mare as defined above, with (a) a chloroformate of the formula ClC(O)OR⁴,where R⁴ is as defined above, or (b) a dicarbonate of the formula R⁴OC(O)OC(O)OR⁴, where R⁴ is as defined above.

4. Alternatively, the process for the preparation of the compounds ofthe formula (Ib), which comprises:

reacting a compound of the formula ##STR12## wherein R¹, R², R³ and mare as defined above, and --C(O)Z is an activated carbonyl complex whereZ is as defined supra, with an appropriate alcohol of the formula R⁴ OH,where R⁴ is as defined above.

The following specific description is given to enable those skilled inthe art to more clearly understand and practice the present invention.It should not be considered as a limitation upon the scope of theinvention but merely as illustrative and representative thereof.

Preparation 1 Preparation of 2,3-dimethoxy-1,4-naphthoquinone andrelated compounds of formula (IV)

To a mechanically stirred solution of sodium methoxide (11.1 g) inanhydrous methanol (200 mL) under a blanket of nitrogen was added2,3-dichloro-1,4-naphthoquinone (22.7 g) as rapidly as possible. Thetemperature rose to 50° C. during the addition, and the reaction wasthen heated to reflux for 1 hour. The mixture was cooled and acidifiedwith 6M hydrochloric acid to give a brilliant yellow color. After theaddition of water (800 mL), the reaction mixture was filtered, and theprecipitate was washed with aqueous methanol (4:1 water-methanol) untilthe filtrate was yellow-orange. The precipitate was air dried to yield21.2 g of 2,3-dimethoxy-1,4-naphthoquinone, m.p. 116°-117° C.

Similarly, optionally substituting the appropriate sodium alkoxide forsodium methoxide and optionally substituting the appropriate compound offormula (III) for 2,3-dichloro-1,4-naphthoquinone, the followingcompounds are prepared:

2,3-diethoxy-1,4-naphthoquinone;

2,3-di-n-propoxy-1,4-naphthoquinone;

6-chloro-2,3-dimethoxy-1,4-naphthoquinone;

6,7-dimethyl-2,3-dimethoxy-1,4-naphthoquinone;

6-bromo-2,3-dimethoxy-1,4-naphthoquinone;

6-fluoro-2,3-dimethoxy-1,4-naphthoquinone;

6-chloro-2,3-diethoxy-1,4-naphthoquinone;

6-methyl-2,3-dimethoxy-1,4-naphthoquinone;

6-i-propyl-2,3-dimethoxy-1,4-naphthoquinone;

6-phenyl-2,3-dimethoxy-1,4-naphthoquinone;

6-benzyl-2,3-dimethoxy-1,4-naphthoquinone;

2,3-di-n-butoxy-6-chloro-1,4-naphthoquinone;

6-chloro-2,3-di-i-butoxy-1,4-naphthoquinone;

6-chloro-2,3-(2,2-dimethylpropoxy)-1,4-naphthoquinone;

2,3-di-s-butoxy-1,4-naphthoquinone;

2,3-di(2,2-dimethylpropoxy)-1,4-naphthoquinone;

2,3-di-n-hexyloxy-1,4-naphthoquinone;

2,3-di-n-butoxy-1,4-naphthoquinone;

2,3-diphenoxy-1,4-naphthoquinone;

6-chloro-2,3-diphenoxy-1,4-naphthoquinone;

6-chloro-2,3-di(4-ethylphenoxy)-1,4-naphthoquinone;

6-chloro-2,3-di(2-fluorophenoxy)-1,4-naphthoquinone;

6-chloro-2,3-di(4-t-butylphenoxy)-1,4-naphthoquinone;

6-chloro-2,3-di(2,6-dimethylphenoxy)-1,4-naphthoquinone; and

6-chloro-2,3-di(2-ethoxyphenoxy)-1,4-naphthoquinone.

Preparation 2 Preparation of 2-ethyl-1,4-naphthoquinone and relatedcompounds of formula (II)

A solution of 1,4-naphthoquinone (7.91 g), propanoic acid (3.70 g) andsilver nitrate (1.53 g) in a mixture of acetonitrile (11.4 mL),sulfolane (34.1 mL) and water (79.5 mL) was heated at 60°-65° C. for 2hours. A solution of ammonium persulfate (13.7 g) in water (25 mL) wasthen added dropwise. The mixture was cooled in ice water and extractedwith ether. The organic layer was washed with saturated sodiumbicarbonate, water and brine, then dried, filtered and evaporated.Chromatography over silica gel afforded 2-ethyl-1,4-naphthoquinone, m.p.87°-88° C.

Similarly, using the above procedure but optionally replacing1,4-naphthoquinone with an appropriately substituted 1,4-naphthoquinone,or optionally replacing propanoic acid with an appropriate carboxylicacid, the following compounds may be prepared:

2-methyl-1,4-naphthoquinone;

2-n-propyl-1,4-naphthoquinone;

2,6-dimethyl-1,4-naphthoquinone;

2-ethyl-5-methyl-1,4-naphthoquinone;

2-sec-butyl-1,4-naphthoquinone;

2-n-pentyl-1,4-naphthoquinone;

2-ethyl-5-fluoro-1,4-naphthoquinone;

3-ethyl-6-methoxy-1,4-naphthoquinone;

2-methyl-6-benzyloxy-1,4-naphthoquinone;

2-ethyl-6-methoxy-1,4-naphthoquinone;

2-methyl-6-fluoro-1,4-naphthoquinone;

2-isopropyl-1,4-naphthoquinone;

2-n-hexyl-1,4-naphthoquinone;

2-methyl-6-chloro-1,4-naphthoquinone;

2,5-dimethyl-1,4-naphthoquinone;

2-methyl-6-phenyl-1,4-naphthoquinone;

2-methyl-5-methoxy-1,4-naphthoquinone;

2-methyl-5-ethoxy-1,4-naphthoquinone;

2-methyl-6-benzyloxy-1,4-naphthoquinone;

2-ethyl-5-chloro-1,4-naphthoquinone;

2-isopropyl-5-phenyl-1,4-naphthoquinone;

2-n-hexyl-6-methyl-1,4-naphthoquinone;

2-n-propyl-6-chloro-1,4-naphthoquinone;

2-n-propyl-6-fluoro-1,4-naphthoquinone;

2-phenyl-1,4-naphthoquinone;

2,6,7-trimethyl-1,4-naphthoquinone;

2-t-butyl-1,4-naphthoquinone; and

2-n-propyl-6-methyl-1,4-naphthoquinone.

Preparation 3A Preparation of compounds of formula (VII)

A. Chlorine was bubbled through a solution of 1,4-naphthoquinone (39.5g) in glacial acetic acid maintained at 15° C. by cooling. Theprecipitated intermediate dichloride was isolated by filtration and thensuspended in fresh glacial acetic acid (500 mL). Anhydrous sodiumacetate (25 g) was added, and the mixture was brought to reflux. Waterwas then added, and the mixture was allowed to cool, precipitating2-chloro-1,4-naphthoquinone, collected by filtration and air drying,m.p. 118° C.

B. 2-Chloro-3-methyl-1,4-naphthoquinone was prepared analogously, exceptthat the intermediate dichloride was isolated as an oil afterevaporation, aqueous extraction with ether and evaporation. Conversionof this intermediate using sodium acetate in acetic acid gave2-chloro-3-methyl-1,4-naphthoquinone, m.p. 155°-156° C.

C. Similarly, using the procedure in paragraph A above, but optionallyreplacing 1,4-naphthoquinone with an appropriately substituted1,4-naphthoquinone, the following compounds may be prepared:

2-chloro-3,8-dimethyl-1,4-naphthoquinone;

2-chloro-3-methyl-8-methoxy-1,4-naphthoquinone;

2-chloro-3-methyl-7-benzyloxy-1,4-naphthoquinone;

2-chloro-3-ethyl-8-chloro-1,4-naphthoquinone;

2-chloro-3-isopropyl-8-phenyl-1,4-naphthoquinone;

2-chloro-3-n-hexyl-7-methyl-1,4-naphthoquinone;

2-chloro-3-n-propyl-7-chloro-1,4-naphthoquinone;

2-chloro-3-n-propyl-7-fluoro-1,4-naphthoquinone;

2,6-dichloro-1,4-naphthoquinone;

2,5-dichloro-1,4-naphthoquinone;

2-chloro-6-methoxy-1,4-naphthoquinone;

2-chloro-6-ethoxy-1,4-naphthoquinone;

2-chloro-6-methyl-1,4-naphthoquinone;

2-chloro-6-ethyl-1,4-naphthoquinone;

2-chloro-3-ethyl-1,4-naphthoquinone;

2-chloro-3-n-propyl-1,4-naphthoquinone;

2-chloro-3,7-dimethyl-1,4-naphthoquinone;

2-chloro-3-ethyl-8-methyl-1,4-naphthoquinone;

2-chloro-3-phenyl-1,4-naphthoquinone;

2-chloro-3-isopropyl-1,4-naphthoquinone;

2-chloro-3-sec-butyl-1,4-naphthoquinone;

2-chloro-3-n-pentyl-1,4-naphthoquinone;

2-chloro-3-n-hexyl-1,4-naphthoquinone;

2-chloro-3-ethyl-8-fluoro-1,4-naphthoquinone;

2-chloro-3-methyl-7-phenyl-1,4-naphthoquinone;

2-chloro-6-bromo-1,4-naphthoquinone;

2-chloro-6-fluoro-1,4-naphthoquinone;

2-chloro-6-methyl-1,4-naphthoquinone;

2-chloro-6-i-propyl-1,4-naphthoquinone;

2-chloro-6-phenyl-1,4-naphthoquinone;

2-chloro-6-benzyl-1,4-naphthoquinone;

2-chloro-6,7-dimethyl-1,4-naphthoquinone;

2-chloro-5-methoxy-1,4-naphthoquinone;

2-chloro-5-phenyl-1,4-naphthoquinone;

2,7-dichloro-1,4-naphthoquinone;

2-chloro-7-methyl-1,4-naphthoquinone;

2-chloro-3-ethyl-1,4-naphthoquinone;

2-chloro-3-methyl-1,4-naphthoquinone;

2-chloro-3-ethyl-7-methoxy-1,4-naphthoquinone;

2-chloro-3-methyl-6-ethoxy-1,4-naphthoquinone;

2-chloro-3-methyl-7-benzyloxy-1,4-naphthoquinone;

2,6-dichloro-3-methyl-1,4-naphthoquinone;

2-chloro-3,6,7-trimethyl-1,4-naphthoquinone;

2-chloro-3-n-propyl-7-methyl-1,4-naphthoquinone;

2-chloro-3-t-butyl-1,4-naphthoquinone; and

2,6-dichloro-3-n-propyl-1,4-naphthoquinone.

Preparation 3B Preparation of compounds of formula (III)

A. Chlorine was bubbled through a solution of 1,4-naphthoquinone (16.0g) and iodine (1.20 g) in glacial acetic acid while refluxing themixture for 2 hours. Water was then added, and the mixture was allowedto cool, precipitating 2,3-dichloro-1,4-naphthoquinone, collected byfiltration and air drying, m.p. 147°-148° C.

B. Similarly, using the procedure in paragraph A above, but optionallyreplacing 1,4-naphthoquinone with an appropriately substituted1,4-naphthoquinone, the following compounds may be prepared:

2,3,6-trichloro-1,4-naphthoquinone;

2,3-dichloro-6-fluoro-1,4-naphthoquinone;

2,3-dichloro-6-methoxy-1,4-naphthoquinone;

2,3-dichloro-6-methyl-1,4-naphthoquinone;

2,3-dichloro-6,7-dimethyl-1,4-naphthoquinone; and

2,3-dichloro-6-phenyl-1,4-naphthoquinone.

Preparation 4 Preparation of compounds of formula (VIII)

A. A solution of 2-chloro-1,4-naphthoquinone (10.3 g) in tetrahydrofuran(100 mL) was treated with a suspension of sodium methoxide (3.20 g) intetrahydrofuran (25 mL) at room temperature. After stirring overnight,the mixture was evaporated, and the residue was taken up in ether. Theorganic layer was washed with brine, dried, filtered and evaporated.Chromatography over silica gel gave 2-methoxy-1,4-naphthoquinone, m.p.182°-183° C.

B. Similarly, replacing the 2-chloro-1,4-naphthoquinone with othercompounds of formula (VII) and following the above procedure, thefollowing compounds were prepared:

2-ethoxy-1,4-naphthoquinone, m.p. 122°-123° C.;

2-methoxy-3-methyl-1,4-naphthoquinone, m.p. 93°-94° C.;

2-n-propoxy-1,4-naphthoquinone, m.p. 93°-94° C.;

2-isopropoxy-3-methyl-1,4-naphthoquinone, m.p. 114°-115° C.;

2-n-butoxy-1,4-naphthoquinone, m.p. 110°-111° C.;

2-ethoxy-3-methyl-1,4-naphthoquinone, m.p. 67°-68° C.;

2-n-propoxy-3-methyl-1,4-naphthoquinone, oil; and

2-isopropoxy-3-methyl-1,4-naphthoquinone, oil.

C. Similarly, replacing the 2-chloro-1,4-naphthoquinone with othercompounds of formula (VII) and following the above procedure, thefollowing compounds are prepared:

2-methoxy-3,8-dimethyl-1,4-naphthoquinone;

2,8-dimethoxy-3-methyl-1,4-naphthoquinone;

2-methoxy-3-methyl-7-benzyloxy-1,4-naphthoquinone;

2-methoxy-3-ethyl-8-chloro-1,4-naphthoquinone;

2-methoxy-3-isopropyl-8-phenyl-1,4-naphthoquinone;

2-methoxy-3-n-hexyl-7-methyl-1,4-naphthoquinone;

2-methoxy-3-n-propyl-7-chloro-1,4-naphthoquinone;

2-methoxy-3-n-propyl-7-fluoro-1,4-naphthoquinone;

2-methoxy-6-chloro-1,4-naphthoquinone;

2-methoxy-5-chloro-1,4-naphthoquinone;

2,6-dimethoxy-1,4-naphthoquinone;

2-methoxy-6-ethoxy-1,4-naphthoquinone;

2-methoxy-6-methyl-1,4-naphthoquinone;

2-methoxy-6-ethyl-1,4-naphthoquinone;

2-methoxy-3-ethyl-1,4-naphthoquinone;

2-methoxy-3-n-propyl-1,4-naphthoquinone;

2-methoxy-3,7-dimethyl-1,4-naphthoquinone;

2-methoxy-3-ethyl-8-methyl-1,4-naphthoquinone;

2-methoxy-3-phenyl-1,4-naphthoquinone;

2-methoxy-3-isopropyl-1,4-naphthoquinone;

2-methoxy-3-sec-butyl-1,4-naphthoquinone;

2-methoxy-3-n-pentyl-1,4-naphthoquinone;

2-methoxy-3-n-hexyl-1,4-naphthoquinone;

2-methoxy-3-ethyl-8-fluoro-1,4-naphthoquinone;

2-methoxy-3-methyl-7-phenyl-1,4-naphthoquinone;

2-methoxy-6-bromo-1,4-naphthoquinone;

2-methoxy-6-fluoro-1,4-naphthoquinone;

2-methoxy-6-methyl-1,4-naphthoquinone;

2-methoxy-6-i-propyl-1,4-naphthoquinone;

2-methoxy-6-phenyl-1,4-naphthoquinone;

2-methoxy-6-benzyl-1,4-naphthoquinone;

2-methoxy-6,7-dimethyl-1,4-naphthoquinone;

2,5-dimethoxy-1,4-naphthoquinone;

2-methoxy-5-phenyl-1,4-naphthoquinone;

2-methoxy-7-chloro-1,4-naphthoquinone;

2-methoxy-7-methyl-1,4-naphthoquinone;

2-methoxy-3-ethyl-1,4-naphthoquinone;

2-methoxy-3-t-butyl-1,4-naphthoquinone;

2,7-dimethoxy-3-ethyl-1,4-naphthoquinone;

2-methoxy-3-methyl-6-ethoxy-1,4-naphthoquinone;

2-methoxy-3-methyl-7-benzyloxy-1,4-naphthoquinone;

2-methoxy-6-chloro-3-methyl-1,4-naphthoquinone;

2-methoxy-3,6,7-trimethyl-1,4-naphthoquinone;

2-methoxy-3-n-propyl-7-methyl-1,4-naphthoquinone;

2-methoxy-6-chloro-3-n-propyl-1,4-naphthoquinone;

2-ethoxy-3-ethyl-1,4-naphthoquinone;

2-ethoxy-3-n-propyl-1,4-naphthoquinone;

2-ethoxy-3-isobutyl-1,4-naphthoquinone;

2-ethoxy-6-bromo-1,4-naphthoquinone;

2-ethoxy-6-fluoro-1,4-naphthoquinone;

2-ethoxy-6-methyl-1,4-naphthoquinone;

2-ethoxy-6-i-propyl-1,4-naphthoquinone;

2-ethoxy-6-phenyl-1,4-naphthoquinone;

2-ethoxy-6-benzyl-1,4-naphthoquinone;

2-ethoxy-6,7-dimethyl-1,4-naphthoquinone;

2-ethoxy-5-methoxy-1,4-naphthoquinone;

2-ethoxy-5-phenyl-1,4-naphthoquinone;

2-ethoxy-6-chloro-1,4-naphthoquinone;

2-ethoxy-7-methyl-1,4-naphthoquinone;

2-ethoxy-3-ethyl-5-fluoro-1,4-naphthoquinone;

2-ethoxy-3-methyl-5-phenyl-1,4-naphthoquinone;

2-n-propoxy-3-ethyl-1,4-naphthoquinone;

2-n-propoxy-3-n-propyl-1,4-naphthoquinone;

2-n-propoxy-3-n-hexyl-1,4-naphthoquinone;

2-isopropoxy-3-ethyl-1,4-naphthoquinone;

2-isopropoxy-3-n-propyl-1,4-naphthoquinone;

2-isopropoxy-3-n-hexyl-1,4-naphthoquinone;

2-n-butoxy-3-methyl-1,4-naphthoquinone;

2-n-butoxy-3-ethyl-1,4-naphthoquinone;

2-s-butoxy-1,4-naphthoquinone;

2-n-pentyloxy-1,4-naphthoquinone;

2-n-pentyloxy-3-methyl-1,4-naphthoquinone;

2-s-pentyloxy-1,4-napthoquinone;

2-n-hexyloxy-1,4-naphthoquinone;

2-n-hexyloxy-3-methyl-1,4-naphthoquinone;

2(2,2-dimethylpropoxy)-1,4-naphthoquinone;

2-phenoxy-1,4-naphthoquinone;

2-(4-chlorophenoxy)-1,4-naphthoquinone;

2-(4-methoxyphenoxy)-1,4-naphthoquinone;

2-(2,4-dichlorophenoxy)-1,4-naphthoquinone;

2-t-butyloxy-1,4-naphthoquinone; and

2-(3-methylphenoxy)-1,4-naphthoquinone.

Preparation 5 Preparation of 2-methoxy-1,4-dihydroxynaphthalene andrelated compounds of formula (V)

A. A solution of 2-methoxy-1,4-naphthoquinone (20.0 g) intetrahydrofuran (150 mL) was hydrogenated at atmospheric pressure overPd-C (10%, 0.5 g) until the calculated amount of hydrogen was absorbed,approximately 4 hours. Filtering off the catalyst under an atmosphere ofnitrogen gave a solution of the desired product, which was used as suchwithout isolation of the product as the starting material in Examples 1,2 and 3, infra. Alternatively, the solvent is removed under reducedpressure and the residue recrystallized from diethyl ether/pentane,affording 2-methoxy-1,4-dihydroxynaphthalene.

B. Similarly, proceeding as above, substituting the appropriate compoundof formula (IV) or (VIII) for 2-methoxy-1,4-naphthoquinone, thefollowing compounds, for example, were prepared:

2,3-dimethoxy-1,4-dihydroxynaphthalene.

2,3-dimethoxy-1,4-dihydroxy-6-chloronaphthalene.

2,3-diphenoxy-1,4-dihydroxynaphthalene.

2,3-diphenoxy-1,4-dihydroxy-6-chloronaphthalene.

2-methoxy-3-methyl-1,4-dihydroxynaphthalene.

C. Similarly proceeding as above, substituting the appropriate compoundof formula (IV) or (VIII) for 2-methoxy-1,4-naphthoquinone, thefollowing compounds of formula (V), for example, are prepared:

2-methoxy-3,8-dimethyl-1,4-dihydroxynaphthalene;

2,8-dimethoxy-3-methyl-1,4-dihydroxynaphthalene;

2-methoxy-3-methyl-7-benzyloxy-1,4-dihydroxynaphthalene;

2-methoxy-3-ethyl-8-chloro-1,4-dihydroxynaphthalene;

2-methoxy-3-isopropyl-8-phenyl-1,4-dihydroxynaphthalene;

2-methoxy-3-t-butyl-1,4-dihydroxynaphthalene;

2-methoxy-3-n-hexyl-7-methyl-1,4-dihydroxynaphthalene;

2-methoxy-3-n-propyl-7-chloro-1,4-dihydroxynaphthalene;

2-methoxy-3-n-propyl-7-fluoro-1,4-dihydroxynaphthalene;

2-methoxy-6-chloro-1,4-dihydroxynaphthalene;

2-methoxy-5-chloro-1,4-dihydroxynaphthalene;

2,6-dimethoxy-1,4-dihydroxynaphthalene;

2-methoxy-6-ethoxy-1,4-dihydroxynaphthalene;

2-methoxy-6-methyl-1,4-dihydroxynaphthalene;

2-methoxy-6-ethyl-1,4-dihydroxynaphthalene;

2-methoxy-3-ethyl-1,4-dihydroxynaphthalene;

2-methoxy-3-n-propyl-1,4-dihydroxynaphthalene;

2-methoxy-3,7-dimethyl-1,4-dihydroxynaphthalene;

2-methoxy-3-ethyl-8-methyl-1,4-dihydroxynaphthalene;

2-methoxy-3-phenyl-1,4-dihydroxynaphthalene;

2-methoxy-3-isopropyl-1,4-dihydroxynaphthalene;

2-methoxy-3-sec-butyl-1,4-dihydroxynaphthalene;

2-methoxy-3-n-pentyl-1,4-dihydroxynaphthalene;

2-methoxy-3-n-hexyl-1,4-dihydroxynaphthalene;

2-methoxy-3-ethyl-8-fluoro-1,4-dihydroxynaphthalene;

2-methoxy-3-methyl-7-phenyl-1,4-dihydroxynaphthalene;

2-methoxy-6-bromo-1,4-dihydroxynaphthalene;

2-methoxy-6-fluoro-1,4-dihydroxynaphthalene;

2-methoxy-6-methyl-1,4-dihydroxynaphthalene;

2-methoxy-6-i-propyl-1,4-dihydroxynaphthalene;

2-methoxy-6-phenyl-1,4-dihydroxynaphthalene;

2-methoxy-6-benzyl-1,4-dihydroxynaphthalene;

2-methoxy-6,7-dimethyl-1,4-dihydroxynaphthalene;

2,5-dimethoxy-1,4-dihydroxynaphthalene;

2-methoxy-5-phenyl-1,4-dihydroxynaphthalene;

2-methoxy-7-chloro-1,4-dihydroxynaphthalene;

2-methoxy-7-methyl-1,4-dihydroxynaphthalene;

2-methoxy-3-ethyl-1,4-dihydroxynaphthalene;

2-methoxy-3-methyl-1,4-dihydroxynaphthalene;

2,7-dimethoxy-3-ethyl-1,4-dihydroxynaphthalene;

2-methoxy-3-methyl-6-ethoxy-1,4-dihydroxynaphthalene;

2-methoxy-3-methyl-7-benzyloxy-1,4-dihydroxynaphthalene;

2-methoxy-6-chloro-3-methyl-1,4-dihydroxynaphthalene;

2-methoxy-3,6,7-trimethyl-1,4-dihydroxynaphthalene;

2-methoxy-3-n-propyl-7-methyl-1,4-dihydroxynaphthalene;

2-methoxy-6-chloro-3-n-propyl-1,4-dihydroxynaphthalene;

2-ethoxy-1,4-dihydroxynaphthalene;

2-ethoxy-3-methyl-1,4-dihydroxynaphthalene;

2-ethoxy-3-ethyl-1,4-dihydroxynaphthalene;

2-ethoxy-3-n-propyl-1,4-dihydroxynaphthalene;

2-ethoxy-3-isobutyl-1,4-dihydroxynaphthalene;

2-ethoxy-6-bromo-1,4-dihydroxynaphthalene;

2-ethoxy-6-fluoro-1,4-dihydroxynaphthalene;

2-ethoxy-6-methyl-1,4-dihydroxynaphthalene;

2-ethoxy-6-i-propyl-1,4-dihydroxynaphthalene;

2-ethoxy-6-phenyl-1,4-dihydroxynaphthalene;

2-ethoxy-6-benzyl-1,4-dihydroxynaphthalene;

2-ethoxy-6,7-dimethyl-1,4-dihydroxynaphthalene;

2-ethoxy-5-methoxy-1,4-dihydroxynaphthalene;

2-ethoxy-5-phenyl-1,4-dihydroxynaphthalene;

2-ethoxy-6-chloro-1,4-dihydroxynaphthalene;

2-ethoxy-7-methyl-1,4-dihydroxynaphthalene;

2-ethoxy-3-ethyl-5-fluoro-1,4-dihydroxynaphthalene;

2-ethoxy-3-methyl-5-phenyl-1,4-dihydroxynaphthalene;

2-n-propoxy-1,4-dihydroxynaphthalene;

2-n-propoxy-1,4-dihydroxynaphthalene;

2-n-propoxy-3-ethyl-1,4-dihydroxynaphthalene;

2-n-propoxy-3-n-propyl-1,4-dihydroxynaphthalene;

2-n-butoxy-1,4-dihydroxynaphthalene;

2-n-butoxy-3-methyl-1,4-dihydroxynaphthalene;

2-t-butoxy-1,4-dihydroxynaphthalene;

2-n-butoxy-3-ethyl-1,4-dihydroxynaphthalene;

2-s-butoxy-1,4-dihydroxynaphthalene;

2-n-pentyloxy-1,4-dihydroxynaphthalene;

2-n-pentyloxy-3-methyl-1,4-dihydroxynaphthalene;

2-s-pentyloxy-1,4-dihydroxynaphthalene;

2-n-hexyloxy-1,4-dihydroxynaphthalene;

2-n-hexyloxy-3-methyl-1,4-dihydroxynaphthalene;

2(2,2-dimethylpropoxy)-1,4-dihydroxynaphthalene;

2-phenoxy-1,4-dihydroxynaphthalene;

2-(4-chlorophenoxy)-1,4-dihydroxynaphthalene;

2-(4-methoxyphenoxy)-1,4-dihydroxynaphthalene;

2-(2,4-dichlorophenoxy)-1,4-dihydroxynaphthalene;

2-(3-methylphenoxy)-1,4-dihydroxynaphthalene;

2,3-dimethoxy-1,4-dihydroxy-6-chloronaphthalene;

2,3-dimethoxy-1,4-dihydroxy-6-bromonaphthalene;

2,3-dimethoxy-1,4-dihydroxy-6-fluoronaphthalene;

2,3-dimethoxy-1,4-dihydroxy-6-ethoxynaphthalene;

2,3-dimethoxy-1,4-dihydroxy-6-phenylnaphthalene;

2,3-dimethoxy-1,4-dihydroxy-6,7-dimethylnaphthalene;

2,3-diethoxy-1,4-dihydroxynaphthalene;

2,3-diethoxy-1,4-dihydroxy-6-chloronaphthalene;

2,3-diethoxy-1,4-dihydroxy-6-methoxynaphthalene;

2,3-di-n-propoxy-1,4-dihydroxynaphthalene;

2,3-diisopropoxy-1,4-dihydroxynaphthalene;

2,3-di-n-butoxy-1,4-dihydroxynaphthalene;

2,3-di-n-hexyloxy-1,4-dihydroxynaphthalene;

2,3-di(2-methylhexyloxy)-1,4-dihydroxynaphthalene;

2,3-di(4-chlorophenoxy)-1,4-dihydroxynaphthalene;

2,3-di(4-methoxyphenoxy)-1,4-dihydroxynaphthalene;

2,3-di(2,4-dichlorophenoxy)-1,4-dihydroxynaphthalene; and

2,3-di(3-methylphenoxy)-1,4-dihydroxynaphthalene.

EXAMPLE 1 Preparation of2,3-dimethoxy-1,4-di(methylcarbamoyloxy)naphthalene and relatedcompounds of formula (Ia) where R⁶ is hydrogen

A. To a solution of 1.00 g of 2,3-dimethoxy-1,4-dihydroxynaphthalene,prepared as shown in Preparation 5, in 50 ml of tetrahydrofuran wasadded 0.670 g of methyl isocyanate followed by 0.12 g of4-dimethylaminopyridine. The solution was stirred at room temperatureovernight. The solvent was removed under reduced pressure and theresidue dissolved in ethyl acetate, washed with dilute hydrochloric acidand dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue chromotographed on silica gel, elutingwith methylene chloride, giving2,3-dimethoxy-1,4-di(methylcarbamoyloxy)naphthalene, m.p. 228°-229° C.

B. Similarly, starting with the appropriate compound of formula (V) andthe appropriate isocyanate, the following compounds of formula (Ia) wereprepared:

2,3-dimethoxy-1,4-di(ethylcarbamoyloxy)naphthalene, m.p. 198°-199° C.

2,3-dimethoxy-1,4-di(methylcarbamoyloxy)-6-chloronaphthalene, m.p.185°-187° C.

2,3-dimethoxy-1,4-di(ethylcarbamoyloxy)-6-chloronaphthalene, m.p.197°-198° C.

2,3-diphenoxy-1,4-di(methylcarbamoxyloxy)naphthalene, m.p. 245°-246° C.

2,3-diphenoxy-1,4-di(methylcarbamoyloxy)-6-chloronaphthalene, m.p.226°-227° C.

2-methoxy-1,4-di(methylcarbamoyloxy)naphthalene, m.p. 199°-200° C.

2-methoxy-3-methyl-1,4-di(methylcarbamoyloxy)naphthalene, m.p. 255°-256°C.

C. Similarly, starting with the appropriate compound of formula (V) andthe appropriate isocyanate, the following exemplary compounds of formula(Ia) are prepared:

2,3-dimethoxy-1,4-di(methylcarbamoyloxy)-6-bromonaphthalene;

2,3-dimethoxy-1,4-di(ethylcarbamoyloxy)-6-fluoronaphthalene;

2,3-dimethoxy-1,4-di(methylcarbamoyloxy)-6,7-dimethylnaphthalene;

2,3-dimethoxy-1,4-di(ethylcarbamoyloxy)-6-phenylnaphthalene;

2,3-dimethoxy-1,4-di(n-propylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(isopropylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(n-butylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(n-hexylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(2-methylhexylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(cyclohexylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(phenylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(benzylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-di(methylcarbamoyloxy)-6-chloronaphthalene;

2,3-diethoxy-1,4-di(ethylcarbamoyloxy)-6-fluoronaphthalene;

2,3-diethoxy-1,4-di(methylcarbamoyloxy)-6,7-dimethylnaphthalene;

2,3-diethoxy-1,4-di(ethylcarbamoyloxy)-6-phenylnaphthalene;

2,3-diethoxy-1,4-di(n-propylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-di(isopropylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-di(n-butylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-di(n-hexylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-di(2-methylhexylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-di(cyclohexylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-di(phenylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-di(benzylcarbamoyloxy)naphthalene;

2,3-di-n-propoxy-1,4-di(n-propylcarbamoyloxy)naphthalene;

2,3-di-n-propoxy-1,4-di(n-butylcarbamoyloxy)naphthalene;

2,3-di-n-propoxy-1,4-di(n-hexylcarbamoyloxy)naphthalene;

2,3-di-n-propoxy-1,4-di(cyclohexylcarbamoyloxy)naphthalene;

2,3-di-n-propoxy-1,4-di(phenylcarbamoyloxy)naphthalene;

2,3-diphenoxy-1,4-di(n-propylcarbamoyloxy)naphthalene;

2,3-diphenoxy-1,4-di(isopropylcarbamoyloxy)naphthalene;

2,3-diphenoxy-1,4-di(n-butylcarbamoyloxy)naphthalene;

2,3-diphenoxy-1,4-di(n-hexylcarbamoyloxy)naphthalene;

2,3-diphenoxy-1,4-di(2-methylhexylcarbamoyloxy)naphthalene;

2,3-diphenoxy-1,4-di(cyclohexylcarbamoyloxy)naphthalene;

2,3-diphenoxy-1,4-di(phenylcarbamoyloxy)naphthalene;

2,3-diphenoxy-1,4-di(benzylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(n-propylcarbamoyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(isopropylcarbamoyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(n-butylcarbamoyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(n-hexylcarbamoyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(2-methylhexylcarbamoyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(cyclohexylcarbamoyloxy)-6-chloronapthalene;

2,3-dimethoxy-1,4-di(phenylcarbamoyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(benzylcarbamoyloxy)-6-chloronaphthalene;

2,3-diethoxy-1,4-di(n-propylcarbamoyloxy)-6-chloronaphthalene;

2,3-diethoxy-1,4-di(isopropylcarbamoyloxy)-6-methylnaphthalene;

2,3-diethoxy-1,4-di(n-butylcarbamoyloxy)-6-methoxynaphthalene;

2,3-diethoxy-1,4-di(n-hexylcarbamoyloxy)-6-fluoronaphthalene;

2,3-diethoxy-1,4-di(2-methylhexycarbamoyloxy)-5,6-dimethylnaphthalene;

2,3-di-n-propoxy-1,4-di(cyclohexylcarbamoyloxy)-6-chloronaphthalene;

2,3-di-n-butoxy-1,4-di(phenylcarbamoyloxy)-6-chloronaphthalene;

2,3-diphenoxy-1,4-di(benzylcarbamoyloxy)-6-chloronaphthalene;

2-methoxy-3-methyl-1,4-di(ethylcarbamoyloxy)naphthalene;

2-methoxy-3-methyl-1,4-di(methylcarbamoyloxy)-6-chloronaphthalene;

2-methoxy-3-methyl-1,4-di(methylcarbamoyloxy)-7-bromonaphthalene;

2-methoxy-3-methyl-1,4-di-(methylcarbamoyloxy)-6-fluoronaphthalene;

2-methoxy-3methyl-1,4-di(methylcarbamoyloxy)-6-phenylnaphthalene;

2-methoxy-3-methyl-1,4-di(propylcarbamoyloxy)naphthalene;

2-methoxy-3-ethyl-1,4-di(ethylcarbamoyloxy)naphthalene;

2-methoxy-3-methyl-1,4-di(ethylcarbamoyloxy)-6-chloronaphthalene;

2-methoxy-3-methyl-1,4-di(ethylcarbamoyloxy)-7-bromonaphthalene;

2-methoxy-3-propyl-1,4-di(propylcarbamoyloxy)naphthalene;

2-methoxy-3-n-hexyl-1,4-di(methylcarbamoyloxy)naphthalene;

2-methoxy-3-phenyl-1,4-di(methylcarbamoyloxy)naphthalene;

2-methoxy-3-benzyl-1,4-di(methylcarbamoyloxy)naphthalene;

2-methoxy-3-t-butyl-1,4-di(methylcarbamoyloxy)naphthalene;

2-methoxy-3-methyl-1,4-di(methylcarbamoyloxy)-6-chloronaphtahlene;

2methoxy-1,4-di(n-propylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(isopropylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(n-butylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(n-hexylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(2-methylhexylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(cyclohexylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(phenylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(benzylcarbamoyloxy)naphthalene;

2-ethoxy-3-methyl-1,4-di(ethylcarbamoyloxy)naphthalene;

2-ethoxy-3-methyl-1,4-di(propylcarbamoyloxy)naphthalene;

2-ethoxy-3-ethyl-1,4-di(ethylcarbamoyloxy)naphthalene;

2-ethoxy-3-propyl-1,4-di(propylcarbamoyloxy)naphthalene;

2-ethoxy-3-n-hexyl-1,4-di(methylcarbamoyloxy)naphthalene;

2-ethoxy-3-phenyl-1,4-di(methylcarbamoyloxy)naphthalene;

2-ethoxy-3-methyl-1,4-di(methylcarbamoyloxy)-6-chloronaphthalene;

2-ethoxy-1,4-di(n-propylcarbamoyloxy)naphthalene;

2-ethoxy-1,4-di(isopropylcarbamoyloxy)naphthalene;

2-ethoxy-1,4-di(n-butylcarbamoyloxy)naphthalene;

2-ethoxy-1,4-di(n-hexylcarbamoyloxy)naphthalene;

2-ethoxy-1,4-di(2-methylhexylcarbamoyloxy)naphthalene;

2-ethoxy-1,4-di(cyclohexylcarbamoyloxy)naphthalene;

2-ethoxy-1,4-di(phenylcarbamoyloxy)naphthalene;

2-ethoxy-1,4-di(benzylcarbamoyloxy)naphthalene;

2-n-propoxy-1,4-di(n-propylcarbamoyloxy)naphthalene;

2-n-propoxy-1,4-di(n-butylcarbamoyloxy)naphthalene;

2-n-propoxy-1,4-di(n-hexylcarbamoyloxy)naphthalene;

2-n-propoxy-1,4-di(cyclohexylcarbamoyloxy)naphthalene;

2-n-propoxy-1,4-di(phenylcarbamoyloxy)naphthalene;

2-t-butoxy-1,4-di(methylcarbamoyloxy)naphthalene;

2-phenoxy-1,4-di(n-propylcarbamoyloxy)naphthalene;

2-phenoxy-1,4-di(isopropylcarbamoyloxy)naphthalene;

2-phenoxy-1,4-di(n-butylcarbamoyloxy)naphthalene;

2-phenoxy-1,4-di(n-hexylcarbamoyloxy)naphthalene;

2-phenoxy-1,4-di(2-methylhexylcarbamoyloxy)naphthalene;

2-phenoxy-1,4-di(cyclohexylcarbamoyloxy)naphthalene;

2-phenoxy-1,4-di(phenylcarbamoyloxy)naphthalene;

2-phenoxy-1,4-di(benzylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(n-propylcarbamoyloxy)-6-cholornaphthalene;

2-methoxy-1,4-di(isopropylcarbamoyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(n-butylcarbamoyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(n-hexylcarbamoyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(2-methylhexylcarbamoyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(cyclohexylcarbamoyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(phenylcarbamoyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(benzylcarbamoyloxy)-6-chloronaphthalene;

2-ethoxy-1,4-di(n-propylcarbamoyloxy)-6-chloronaphthalene;

2-ethoxy-1,4-di(isopropylcarbamoyloxy)-6-methylnaphthalene;

2-ethoxy-1,4-di(n-butylcarbamoyloxy)-6-methoxynaphthalene;

2-ethoxy-1,4-di(n-hexylcarbamoyloxy)-6-fluoronaphthalene;

2-ethoxy-1,4-di(2-methylhexylcarbamoyloxy)-5,6-dimethylnaphthalene;

2-n-propoxy-1,4-di(cyclohexylcarbamoyloxy)-6-chloronaphthalene;

2-n-butoxy-1,4-di(phenylcarbamoyloxy)-6-chloronaphthalene; and

2-phenoxy-1,4-di(benzylcarbamoyloxy)-6-chloronaphthalene.

EXAMPLE 2 Preparation of2,3-dimethoxy-1,4-bis(dimethylcarbamoyloxy)naphthalene and relatedcompounds of formula (Ia)

A. To a solution of 2.20 g of 2,3-dimethoxy-1,4-dihydroxynaphthalene,prepared as shown in Preparation 5, in 50 ml of dry benzene and 1.6 g ofpyridine is added 16 ml of a solution of 12.5% phosgene in benzene. Themixture is stirred overnight at 25° C., filtered and the filtratecontaining crude 2,3-dimethoxy-1,4-di(chlorocarbonyloxy)naphthalene istreated with a solution of 2.5 g of dimethylamine in 25 ml oftetrahydrofuran. After 4 hours at room temperature the reaction mixtureis diluted with 250 ml of ethyl acetate, washed with dilute hydrochloricacid and dried over magnesium sulfate. The solvent is removed underreduced pressure and the residue chromatographed on silica gel giving2,3-dimethoxy-1,4-bis(dimethylcarbamoyloxy)naphthalene.

B. Similarly, following the procedure of paragraph A above, startingwith the appropriate compound of formula (V) and the appropriate amine,the following compounds of formula (Ia) are prepared:

2,3-dimethoxy-1,4-di(methylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(ethylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(methylcarbamoyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(ethylcarbamoyloxy)-6-chloronaphthalene;

2,3-diphenoxy-1,4-di(methylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(methylcarbamoyloxy)naphthalene;

2-methoxy-3-methyl-1,4-di(methylcaramoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(ethylcarbamoyloxy)-6-fluoronaphthalene;

2,3-dimethoxy-1,4-di(methylcarbamoyloxy)-6,7-dimethylnaphthalene;

2,3-dimethoxy-1,4-di(n-propylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(n-hexylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(phenylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(benzylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(carbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-bis(diethylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-bis(di-n-hexylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(N-methyl-N-hexylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(N-methyl-N-phenylcarbamoyloxy)naphthalene;

2,3-dimethoxy-1,4-di(N-methyl-N-cyclopentylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-di(methylcarbamoyloxy)-6-chloronaphthalene;

2,3-diethoxy-1,4-di(methylcarbamoyloxy)-6,7-dimethylnaphthalene;

2,3-diethoxy-1,4-di(n-hexylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-di(cyclohexylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-dis(diethylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-bis(di-n-hexylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-di(N-methyl-N-hexylcarbamoyloxy)naphthalene;

2,3-diethoxy-1,4-di(N-methyl-N-phenylcarbamoyloxy)naphthalene;

2,3-di-n-propoxy-1,4-di(methylcarbamoyloxy)naphthalene;

2,3-di-n-propoxy-1,4-bis(dimethylcarbamoyloxy)naphthalene;

2-methoxy-3-methyl-1,4-di(methylcarbamoyloxy)-6-chloronaphthalene;

2-methoxy-3-methyl-1,4-bis(dimethycarbamoyloxy)naphthalene;

2-methoxy-3-methyl-1,4-di(methylcarbamoyloxy)-7-chloronaphthalene;

2-methoxy-3-methyl-1,4-di(N-methyl-N-hexylcarbamoyloxy)naphthalene;

2-methoxy-3-methyl-1,4-di(ethylcarbamoyloxy)naphthalene;

2-methoxy-3-methyl-1,4-di(propylcarbamoyloxy)naphthalene;

2-methoxy-3-ethyl-1,4-bis(diethylcarbamoyloxy)naphthalene;

2-methoxy-3-methyl-1,4-di(ethylcarbamoyloxy)-6-chloronaphthalene;

2-methoxy-3-n-hexyl-1,4-di(methylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(n-propylcarbamoyloxy)naphthalene;

2-methoxy-1,4-bis(dimethylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(N-methyl-N-butylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(n-hexylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(N-ethyl-N-hexylcarbamoyloxy)naphthalene;

2-methoxy-1,4-bis(dicyclohexylcarbamoyloxy)naphthalene;

2-ethoxy-1,4-di(n-propylcarbamoyloxy)naphthalene;

2-ethoxy-1,4-bis(dimethylcarbamoyloxy)naphthalene;

2-n-propoxy-1,4-di(N-methyl-N-butylcarbamoyloxy)naphthalene;

2-n-hexyloxy-1,4-di(n-hexylcarbamoyloxy)naphthalene;

2-methoxy-1,4-di(N-ethyl-N-hexylcarbamoyloxy)-6-chloronaphthalene; and

2-methoxy-3-n-hexyl-1,4-bis(dicyclohexylcarbamoyloxy)naphthalene.

EXAMPLE 3 Preparation of 2,3-dimethoxy-1,4-di(methoxycarbonyloxy) andrelated Compounds of Formula (Ib)

A. To a solution of 1.0 g of 2,3-dimethoxy-1,4-dihydroxynaphthalene,prepared as shown in Preparation 5, in 50 ml of tetrahydrofuran wasadded 1.40 g of methyl chloroformate followed by 1.50 g oftriethylamine. The mixture was stirred at room temperature for 16 hours,filtered, then the solvent removed under reduced pressure. The residuewas dissolved in diethyl ether, washed with dilute hydrochloric acid anddried over anhydrous sodium sulfate. The ether was removed under reducedpressure and the residue chromatographed on silica gel, eluting with a1:1 mixture of methylene chloride and hexane, to give2,3-dimethoxy-1,4-di(methoxycarbonyloxy)naphthalene, m.p. 53°-54° C.

B. Similarly, starting with the appropriate compound of formula (V) andthe appropriate chloroformate of formula ClC(O)OR⁴, the followingcompounds of formula (Ib) were prepared:

2,3-dimethoxy-1,4-di(methoxycarbonyloxy)-6-chloronaphthalene, m.p.115°-116° C.

2,3-dimethoxy-1,4-di(ethoxycarbonyloxy)naphthalene, m.p. 94°-95° C.

2,3-dimethoxy-1,4-di(ethoxycarbonyloxy)-6-chloronaphthalene, m.p.94°-95° C.

2,3-dimethoxy-1,4-di(phenoxycarbonyloxy)-6-chloronaphthalene, m.p.199°-200° C.

2,3-diphenoxy-1,4-di(methylcarbonyloxy)naphthalene, m.p. 124°-125° C.

2,3-diphenoxy-1,4-di(methylcarbonyloxy)-6-chloronaphthalene, m.p.106°-107° C.

2-methoxy-1,4-di(methylcarbonyloxy)naphthalene, m.p. 118°-119° C.

2-methoxy-3-methyl-1,4-di(methylcarbonyloxy)naphthalene, m.p. 86°-87° C.

C. Similarly, optionally replacing2,3-dimethoxy-1,4-dihydroxynaphthalene with other compounds of formula(V), prepared as shown in Preparation 5, and optionally replacing methylchloroformate with an appropriately substituted chloroformate of formulaClC(O)OR⁴ or an appropriately substituted dicarbonate of formula R⁴OC(O)OC(O)OR⁴, the following compounds of formula (Ib) are prepared:

2,3-dimethoxy-1,4-di(ethoxycarbonyloxy)naphthalene;

2,3-dimethoxy-1,4-di(methoxycarbonyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(methoxycarbonyloxy)-6-fluoronaphthalene;

2,3-dimethoxy-1,4-di(methoxycarbonyloxy)-6-phenylnaphthalene;

2,3-dimethoxy-1,4-di(methoxycarbonyloxy)-6,7-dimethylnaphthalene;

2,3-dimethoxy-1,4-di(n-propoxycarbonyloxy)naphthalene;

2,3-dimethoxy-1,4-di(isopropoxycarbonyloxy)naphthalene;

2,3-dimethoxy-1,4-di(n-butoxycarbonyloxy)naphthalene;

2,3-dimethoxy-1,4-di(n-hexyloxycarbonyloxy)naphthalene;

2,3-dimethoxy-1,4-di(2-methylhexyloxycarbonyloxy)naphthalene;

2,3-dimethoxy-1,4-di(cyclohexylcarbonyloxy)naphthalene;

2,3-dimethoxy-1,4-di(phenoxycarbonyloxy)naphthalene;

2,3-dimethoxy-1,4-di(benzyloxycarbonyloxy)naphthalene;

2,3-diethoxy-1,4-di(methoxycarbonyloxy)-6-chloronaphthalene;

2,3-diethoxy-1,4-di(methoxycarbonyloxy)-6-fluoronaphthalene;

2,3-diethoxy-1,4-di(methoxycarbonyloxy)-6-phenylnaphthalene;

2,3-diethoxy-1,4-di(methoxycarbonyloxy)-6,7-dimethylnaphthalene;

2,3-diethoxy-1,4-di(n-propoxycarbonyloxy)naphthalene;

2,3-diethoxy-1,4-di(isopropoxycarbonyloxy)naphthalene;

2,3-diethoxy-1,4-di(n-butoxycarbonyloxy)naphthalene;

2,3-diethoxy-1,4-di(n-hexyloxycarbonyloxy)naphthalene;

2,3-diethoxy-1,4-di(2-methylhexyloxycarbonyloxy)naphthalene;

2,3-diethoxy-1,4-di(cyclohexyloxycarbonyloxy)naphthalene;

2,3-diethoxy-1,4-di(phenoxycarbonyloxy)naphthalene;

2,3-diethoxy-1,4-di(benzyloxycarbonyloxy)naphthalene;

2,3-di-n-propoxy-1,4-di(n-propoxycarbonyloxy)naphthalene;

2,3-di-n-propoxy-1,4-di(n-butoxycarbonyloxy)naphthalene;

2,3-di-n-propoxy-1,4-di(n-hexyloxycarbonyloxy)naphthalene;

2,3-di-n-propoxy-1,4-di(cyclohexyloxycarbonyloxy)naphthalene;

2,3-di-n-propoxy-1,4-di(phenoxycarbonyloxy)naphthalene;

2,3-diphenoxy-1,4-di(n-propoxycarbonyloxy)naphthalene;

2,3-diphenoxy-1,4-di(isopropoxycarbonyloxy)naphthalene;

2,3-diphenoxy-1,4-di(n-butoxycarbonyloxy)naphthalene;

2,3-diphenoxy-1,4-di(n-hexyloxycarbonyloxy)naphthalene;

2,3-diphenoxy-1,4-di(2-methylhexyloxycarbonyloxy)naphthalene;

2,3-diphenoxy-1,4-di(cyclohexyloxycarbonyloxy)naphthalene;

2,3-diphenoxy-1,4-di(phenoxycarbonyloxy)naphthalene;

2,3-diphenoxy-1,4-di(benzyloxycarbonyloxy)naphthalene;

2,3-dimethoxy-1,4-di(n-propoxycarbonyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(isopropoxycarbonyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(n-butoxycarbonyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(n-hexyloxycarbonyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(2-methylhexyloxycarbonyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(cyclohexyloxycarbonyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(phenoxycarbonyloxy)-6-chloronaphthalene;

2,3-dimethoxy-1,4-di(benzyloxycarbonyloxy)-6-chloronaphthalene;

2,3-diethoxy-1,4-di(n-propoxycarbonyloxy)-6-chloronaphthalene;

2,3-diethoxy-1,4-di(isopropoxycarbonyloxy)-6-methylnaphthalene;

2,3-diethoxy-1,4-di(n-butoxycarbonyloxy)-6-methoxynaphthalene;

2,3-diethoxy-1,4-di(n-hexyloxycarbonyloxy)-6-fluoronaphthalene;

2,3-diethoxy-1,4-di(2-methylhexyloxycarbonyloxy)-5,6-dimethylnaphthalene;

2,3-di-n-propoxy-1,4-di(cyclohexyloxycarbonyloxy)-6-chloronaphthalene;

2,3-di-n-butoxy-1,4-di(phenoxycarbonyloxy)-6-chloronaphthalene;

2,3-diphenoxy-1,4-di(benzyloxycarbonyloxy)-6-chloronaphthalene;

2-methoxy-3-methyl-1,4-di(ethoxycarbonyloxy)naphthalene;

2-methoxy-3-methyl-1,4-di(propoxycarbonyloxy)naphthalene;

2-methoxy-3-ethyl-1,4-di(ethoxycarbonyloxy)naphthalene;

2-methoxy-3-propyl-1,4-di(propoxycarbonyloxy)naphthalene;

2-methoxy-3-t-butyl-1,4-di(methoxycarbonyloxy)naphthalene;

2-methoxy-3-n-hexyl-1,4-di(methoxycarbonyloxy)naphthalene;

2-methoxy-3-phenyl-1,4-di(methoxycarbonyloxy)naphthalene;

2-methoxy-3-benzyl-1,4-di(methoxycarbonyloxy)naphthalene;

2-methoxy-3-methyl-1,4-di(methoxycarbonyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(n-propoxycarbonyloxy)naphthalene;

2-methoxy-1,4-di(isopropoxycarbonyloxy)naphthalene;

2-methoxy-1,4-di(n-butoxycarbonyloxy)naphthalene;

2-methoxy-1,4-di(n-hexyloxycarbonyloxy)naphthalene;

2-methoxy-1,4-di(2-methylhexyloxycarbonyloxy)naphthalene;

2-methoxy-1,4-di(cyclohexyloxycarbonyloxy)naphthalene;

2-methoxy-1,4-di(phenoxycarbonyloxy)naphthalene;

2-methoxy-1,4-di(benzyloxycarbonyloxy)naphthalene;

2-ethoxy-3-methyl-1,4-di(ethoxycarbonyloxy)naphthalene;

2-ethoxy-3-methyl-1,4-di(propoxycarbonyloxy)naphthalene;

2-ethoxy-3-ethyl-1,4-di(ethoxycarbonyloxy)naphthalene;

2-ethoxy-3-propyl-1,4-di(propoxycarbonyloxy)naphthalene;

2-ethoxy-3-n-hexyl-1,4-di(methoxycarbonyloxy)naphthalene;

2-ethoxy-3-phenyl-1,4-di(methoxycarbonyloxy)naphthalene;

2-ethoxy-3-methyl-1,4-di(methoxycarbonyloxy)-6-chloronaphthalene;

2-ethoxy-1,4-di(n-propoxycarbonyloxy)naphthalene;

2-ethoxy-1,4-di(isopropoxycarbonyloxy)naphthalene;

2-ethoxy-1,4-di(n-butoxycarbonyloxy)naphthalene;

2-ethoxy-1,4-di(n-hexyloxycarbonyloxy)naphthalene;

2-ethoxy-1,4-di(2-methylhexyloxycarbonyloxy)naphthalene;

2-ethoxy-1,4-di(cyclohexoxycarbonyloxy)naphthalene;

2-ethoxy-1,4-di(phenoxycarbonyloxy)naphthalene;

2-ethoxy-1,4-di(benzyloxycarbonyloxy)naphthalene;

2-n-propoxy-1,4-di(n-propoxycarbonyloxy)naphthalene;

2-n-propoxy-1,4-di(n-butoxycarbonyloxy)naphthalene;

2-n-propoxy-1,4-di(n-hexyloxycarbonyloxy)naphthalene;

2-n-propoxy-1,4-di(cyclohexyloxycarbonyloxy)naphthalene;

2-n-propoxy-1,4-di(phenoxycarbonyloxy)naphthalene;

2-t-butoxy-1,4-di(methoxycarbonyloxy)naphthalene;

2-phenoxy-1,4-di(n-propoxycarbonyloxy)naphthalene;

2-phenoxy-1,4-di(isopropoxycarbonyloxy)naphthalene;

2-phenoxy-1,4-di(n-butoxycarbonyloxy)naphthalene;

2-phenoxy-1,4-di(n-hexyloxycarbonyloxy)naphthalene;

2-phenoxy-1,4-di(2-methylhexyloxycarbonyloxy)naphthalene;

2-phenoxy-1,4-di(cyclohexyloxycarbonyloxy)naphthalene;

2-phenoxy-1,4-di(phenoxycarbonyloxy)naphthalene;

2-phenoxy-1,4-di(benzyloxycarbonyloxy)naphthalene;

2-methoxy-1,4-di(n-propoxycarbonyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(isopropoxycarbonyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(n-butoxycarbonyloxy)6-chloronaphthalene;

2-methoxy-1,4-di(n-hexyloxycarbonyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(2-methylhexyloxycarbonyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(cyclohexyloxycarbonyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(phenoxycarbonyloxy)-6-chloronaphthalene;

2-methoxy-1,4-di(benzyloxycarbonyloxy)-6-chloronaphthalene;

2-ethoxy-1,4-di(n-propoxycarbonyloxy)-6-chloronaphthalene;

2-ethoxy-1,4-di(isopropoxycarbonyloxy)-6-methylnaphthalene;

2-ethoxy-1,4-di(n-butoxycarbonyloxy)-6-methoxynaphthalene;

2-ethoxy-1,4-di(n-hexyloxycarbonyloxy)-6-fluoronaphthalene;

2-ethoxy-1,4-di(2-methylhexyloxycarbonyloxy)-5,6-dimethylnaphthalene;

2-n-propoxy-1,4-di(cyclohexyloxycarbonyloxy)-6-chloronaphthalene;

2-n-butoxy-1,4-di(phenoxycarbonyloxy)-6-chloronaphthalene; and

2-phenoxy-1,4-di(benzyloxycarbonyloxy)-6-chloronaphthalene.

EXAMPLE 4 Biological Data 1. Test for Topical Anti-inflammatory Activityby Inhibition of Arachidonic Acid Induced Mouse Ear Edema Materials andMethods

Male or female Swiss Webster mice weighing 18-27 g were randomlyassigned to treatment groups of 8 or 10 animals, caged together, andgiven food and water ad libitum.

The test materials were prepared as solutions or suspensions in reagentgrade acetone at a dose level of 100 mg/ml and arachidonic acid wasprepared as a solution in acetone also at 100 mg/ml. The test materialswere applied to the right ears of mice by means of an automaticmicroliter pipet so that 10 μl of solution was applied to each of theinner and outer surfaces. Each ear therefore received a total of 20 μlof solution containing 2 mg of test material. One hour after applicationof the test material, the arachidonic acid solution was applied in thesame manner. One hour after the arachidonic acid application the animalswere sacrificed by cervical dislocation and the right ears were removed.An 8 mm disc was punched from each ear with a biopsy punch, and thediscs were weighed to the nearest 0.1 mg. For the purpose of determiningthe anti-inflammatory effect of test materials a negative control groupreceiving two applications of acetone only, and a positive control groupreceiving acetone alone followed by arachidonic acid were run in eachexperiment. The percent inhibition resulting from treatment with thetest material was calculated as follows: ##EQU1##

2. Test for Oral Anti-Inflammatory Activity by Oxazolone-Induced DelayedHypersensitivity Mouse Ear Edema Materials and Methods

Female Sim: (SW) fBR mice weighing 23-27 g were used in groups of 10. Ondays 1 and 2 mice received 50 ul of a 2% solution of oxazolone inacetone applied to the unshaved abdomen (sensitization). On day 6 25 ulof a 1.5% solution of oxazolone in acetone was applied to each side ofthe right ear (challenge). Test materials were administered orally inaqueous vehicle 1 hr before challenge and again 6 hr after challenge. Onday 7, 24 hr after challenge, the mice were euthanized and 8 mm diameterplugs obtained from the ears were weighed.

What is claimed is:
 1. A method for treating a mammal having adisease-state which is alleviated by treatment with a lipoxygenaseinhibitor, which comprises systemically administering to said mammal atherapeutically effective amount of a compound of the formula ##STR13##wherein: R¹ is lower alkoxy of one to six carbon atoms or phenoxyoptionally substituted by one or two substituents chosen from loweralkyl of one to four carbon atoms, lower alkoxy of one to four carbonatoms and halo;R² is the same as R¹, or R² is hydrogen, lower alkyl ofone to six carbon atoms, phenyl or phenyl-lower-alkyl, wherein thephenyl ring of the phenyl or phenyl-lower-alkyl group is optionallysubstituted by one or two substituents chosen from lower alkyl of one tofour carbon atoms, lower alkoxy of one to four carbon atoms and halo; R³is hydrogen, halo, lower alkyl of one to six carbon atoms, lower alkoxyof one to six carbon atoms, phenyl, phenyl-lower-alkyl orphenyl-lower-alkoxy, wherein the phenyl ring of the phenyl,phenyl-lower-alkyl or phenyl-lower-alkoxy group is optionallysubstituted by one or two substituents chosen from lower alkyl of one tofour carbon atoms, lower alkoxy of one to four carbon atoms and halo; mis 1 or 2; and both X groups are the same and X is either --C(O)OR⁴ or--C(O)NR⁵ R⁶, wherein R⁴ is alkyl of one to seven carbon atoms, phenylor benzyl, wherein the phenyl ring of the phenyl or benzyl groups isoptionally substituted by one or two substituents chosen from loweralkyl of one to four carbon atoms, lower alkoxy of one to four carbonatoms and halo; and R⁵ and R⁶ are independently hydrogen, lower alkyl ofone to six carbon atoms, cycloalkyl of five to eight carbon atoms orphenyl optionally substituted with one or two substituents chosen fromlower alkyl of one to four carbon atoms, lower alkoxy of one to fourcarbon atoms and halo.
 2. The method of claim 1, wherein saiddisease-state is inflammation.